Bisulfite ion (the aqueous form of the atmospheric pollutant, sulfur dioxide) has three reaction pathways with the major pyrimidine components of nucleic acids: (1) reversible saturation of uracil; (2) deamination of cytosine to uracil; (3) transamination of cytosine to N4-substituted cytoseine derivatives (leading to protein-nucleic acid crosslinking). We propose that one or more of these reactions constitute the principal biochemical lesions inflicted by environmental sulfur dioxide, leading to the adverse effects on health associated with this pollutant. To test this hypothesis, we are investigating these reactions at four distinct levels: (a) Mechanistic studies with nucleosides. (b) (b) Studies on the relation of reactivity to conformation at the polynucleoside level. (c) The effect of bisulfite modification of RNA on protein synthesis, using synthetic messengers, MS2 RNA, and the E. Coli cell-free protein synthesizing system. (d) In vivo studies with bacteria, mammalian cells, and eventually mammals, to measure the extent of nucleic acid modification by bisulfite, and its consequences in terms of inhibition of protein synthesis and killing of cells. We hope that this study will provide concrete data as to the adverse biochemical effects of varying degrees of exposure to sulfur dioxide, and that this will be useful in setting rational guidelines for the control of atmospheric levels of sulfur dioxide.